With the improved survival of HIV-infected patients since the introduction of Highly Active Antiretroviral Therapy (HAART), low bone mass and osteoporotic fractures seem to be emerging as important chronic problems that affect the aging HIV-positive population. Furthermore, an estimated 15 to 30% of HIV-infected patients are co-infected with hepatitis C (HCV), also associated with osteoporosis. For a given decrease in bone mineral density (BMD), the fracture risk increases dramatically with age in the general population. Despite this fact, trends in fracture risk in a large HIV cohort have never been evaluated to determine whether this is a growing problem among HIV-infected patients nor has an in-depth evaluation of risk factors been conducted, including type and duration of antiretroviral therapy (ART) and HCV co-infection. Furthermore, factors associated with HCV infection that might mediate a higher risk of decreased bone density and osteoporotic fractures - either decreased formation or increased resorption - among HIV-infected patients have not been elucidated. Finally, the impact of osteoporotic fractures on AIDS-related and non-AIDS-related morbidity and mortality is not known. We propose to help bridge these gaps in knowledge with a combination of: 1) a retrospective analysis of osteoporotic fracture risk, their predictors and outcomes in the Veterans Health Administration (VHA) Clinical Case Registry (CCR) which contains data on close to 60,000 current and former patients followed since 1984, provides an excellent source for addressing these important questions; and 2) a cross-sectional study comparing BMD and bone turnover markers (BTMs) between HIV/HCV co-infected, HIV and HCV mono-infected patients receiving care at the VA North Texas Health Care System (VANTHCS), with 650 current HIV patients (1/3 co-infected with HCV) and close to 5000 HCV patients. The current proposed work will address three specific aims: 1) To determine the impact of ART on bone health in HIV-infected patients. Using the CCR, osteoporotic fractures will be identified by ICD-9 code. Age-adjusted standardized incidence rates (SIRs) of osteoporotic fractures will be calculated and compared between the pre-HAART (1984-1995) and HAART (1996-2009) eras. Survival analyses will then be performed predicting onset of fractures among HIV-infected patients with various ARTexposure as time-dependent variables; 2) To determine the impact of HCV co-infection on bone health in HIV patients. We will assess BMD, BTMs, calciotropic and gonadal hormones and inflammatory cytokines in HIV/HCV co-infected patients and age-, gender-, and race-matched HIV mono-infected patients and HCV mono-infected patients receiving care at the VANTHCS. The ANOVA analysis will be conducted to detect difference among the three groups of patients. Age-adjusted SIRs of osteoporotic fractures will be computed and compared between HIV/HCV co- infected and HIV-only infected patients. We will further compare the SIRs within the pre-HAART and HAART eras; 3) To determine the association of decreased bone health and osteoporotic fractures with morbidity and mortality of HIV-infected patients. In the cross-sectional analysis, we will evaluate the correlation of dyslipidemia, insulin resistance and hyperlactatemia with BMD and BTMs. Furthermore, we will use the CCR data to explore whether dyslipidemia, hyperglycemia and hyperlactemia predict the onset of osteoporotic fractures by including them into the Cox survival model as time-dependent covariates. Finally, survival models will be constructed from CCR data to explore the association of osteoporotic fractures with all- cause mortality, AIDS and non-AIDS-related mortality.